Treating psychological conditions using muscarinic receptor M1 antagonists

ABSTRACT

Provided are methods of treating psychological diseases and conditions by administration of a preferential muscarinic acetylcholine receptor M 1  antagonist, optionally with at least one antidepressant other than a selective muscarinic acetylcholine receptor M 1  antagonist. The invention also provides for pharmaceutical compositions and kits for administration of at least one selective muscarinic acetylcholine receptor M 1  antagonist in combination with at least one antidepressant other than a selective muscarinic acetylcholine receptor M 1  antagonist.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/805,066, filed Jun. 16, 2006 and U.S. Provisional Application No.60/829,225, filed Oct. 12, 2006, the entire disclosures of both of whichare hereby incorporated herein by reference.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

Not Applicable

FIELD OF THE INVENTION

The present invention relates to the treatment of psychologicaldisorders, including depression, by administration of a selective M₁muscarinic receptor (MIR) antagonist, alone or in combination with anantidepressant.

BACKGROUND OF THE INVENTION

The neurotransmitter acetylcholine (ACh) interacts with two types ofreceptors in effector cell membranes: nicotinic receptors (nAChR), whichare ligand-gated ion channels, and muscarinic receptors (mAChR), whichare G protein-coupled receptors. In mammals five subtypes of mAChR,designated M₁ to M₅, have been identified. The M₁ muscarinic receptor(M₁R) is found in both the central and peripheral nervous systems,particularly the cerebral cortex and sympathetic ganglia. The muscariniceffects mediated by M₁R have been studied largely by use ofM₁R-selective antagonists and, more recently, by the development ofM₁R-null mice.

Although no currently known mAChR antagonists display absoluteselectivity for a single muscarinic receptor subtype, the drugspirenzepine and telenzepine exhibit high relative affinity for M₁R andare therefore often considered M₁R-selective. Pirenzepine is used totreat peptic ulcer disease in Europe, Japan and Canada. Telenzepine hasbeen tested in clinical trials for the same indication. At therapeuticdoses, they moderately reduce gastric acid and pepsin secretion withoutinhibiting smooth muscle activity as do non-selective mAChR antagonists.

There are several lines of evidence suggesting that the M₁R subtype maybe involved in certain aspects of depressive disorders and anxiety.Direct injection of pirenzepine into the nucleus accumbens in theforebrain of rats resulted in increased swimming time in the Porsoltswim test (see, Chau, D. T., et al., Neuroscience, 2001, vol. 104, no.3, pp. 791-8), a common measure of antidepressant activity. M₁R-nullmice also displayed increased swimming time in the Porsolt swim test, aswell as increased social contacts in a social interaction test (see,Miyakawa, T., et al., J. Neurosci., 2001, vol. 21, no. 14, pp. 5239-50).

While pirenzepine and telenzepine are structurally similar to tricyclicantidepressants such as imipramine, they are not known to havepsychotropic effects when taken orally for the treatment of peptic ulcerdisease. In addition, in earlier studies of mice and rats, pirenzepineadministered systemically failed to elicit any behavioral effects (see,Rogoz, Z., Skuza, G., Sowinska, H., Pol. J. Pharmacol. Pharm., 1981,vol. 31, pp. 615-26). The lack of such effects can be explained by theobservation that pirenzepine does not exhibit significant penetration ofthe blood-brain barrier in various species, including rodents and humans(see, Hammer, R., Koss, F. W., Scand. J. GastroenteroL, Suppl., 1979,vol. 14, no. 57, pp. 1-6; Bymaster, F. P., et al., J. Pharmacol. Exp.Ther., 1993, vol. 267, no. 1, pp. 16-24). It is for that reason that theabove-mentioned study of the effect of pirenzepine in the Porsolt swimtest utilized direct injection of the drug into the brain of testanimals.

There exists a need for new and effective medications for the treatmentof psychological conditions, including depression. The present inventionaddresses this and other needs.

BRIEF SUMMARY OF THE INVENTION

The present invention provides methods for treating variouspsychological disorders, including depression, by systemicallyadministering a therapeutically effective amount of one or moremuscarinic M1 receptor (M₁R-selective) antagonists. In practicing thepresent methods, the one or more M₁R-selective antagonists can beadministered without other pharmacological agents or in combination withother pharmacological agents, for example, one or more antidepressantsother than a M₁R-selective antagonist.

Accordingly, in a first aspect, the present invention provides methodsfor treating one or more psychological conditions or disorders bysystemically administering to an individual in need thereof atherapeutically effective amount of one or more selective M₁R-selectiveantagonists, whereby the one or more psychological conditions aretreated.

In a related aspect, the invention provides methods for treating one ormore psychological conditions or disorders by administering to anindividual in need thereof a therapeutically effective amount of acombination of one or more M₁R-selective antagonists and one or moreantidepressants other than a M₁R-selective antagonist, whereby the oneor more psychological conditions are treated.

In one embodiment, the psychological disorder is an affective disorder.In one embodiment, the psychological condition is depression. In oneembodiment, the psychological condition is selected from the groupconsisting of depression, anxiety, social anxiety disorder, agoraphobia,obsessive-compulsive disorder, post-traumatic stress disorder, bodydysmorphic disorder, premenstrual dysphoric disorder, and substanceabuse and/or dependence.

In another aspect, the invention provides pharmaceutical compositionscomprising a mixture of therapeutically effective amounts of one or moreM₁R-selective antagonists and one or more antidepressants other than aM₁R-selective antagonist.

In another aspect, the invention provides kits comprising a mixture oftherapeutically effective amounts of one or more M₁R-selectiveantagonists and one or more antidepressants other than a M₁R-selectiveantagonist.

With regard to the embodiments for carrying out the methods, and for thepharmaceutical compositions and kits, in one embodiment, the one or moreM₁R-selective antagonists is selected from the group consisting ofpirenzepine, telenzepine, and combinations thereof. In one embodiment,the M₁R-selective antagonist is telenzepine (racemic or an opticalisomer). In one embodiment, the M₁R-selective antagonist is pirenzepine.

In one embodiment, the one or more M₁R-selective antagonists areadministered without a second pharmacological agent.

In one embodiment, the one or more M₁R-selective antagonists isadministered in combination with or combined with one or moreantidepressants other than a M₁R-selective antagonist. In oneembodiment, the antidepressant is selected from the group consisting ofa selective serotonin reuptake inhibitor (SSRI) and a selectiveserotonin-norepinephrine reuptake inhibitor (SNRI).

In one embodiment, the antidepressant is a SSRI. In one embodiment, theSSRI is selected from the group consisting of citalopram, escitalopram,fluoxetine, fluvoxamine, paroxetine and sertraline. In one embodiment,the SSRI is selected from the group consisting of citalopram,sertraline, paroxetine, and fluoxetine.

In one embodiment, the antidepressant is a SNRI. In one embodiment, theSNRI is selected from the group consisting of milnacipran, mirtazapine,venlafaxine, duloxetine, desvenlafaxine and sibutramine. In oneembodiment, the SNRI is venlafaxine.

Efficacious results can be achieved without timed administration of theone or more M₁R-selective antagonists. Co-administered active agents,including antidepressants, also provide efficacious results withouttimed administration.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is fluoxetine(racemic or an optical isomer).

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is fluvoxamine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is sertraline orits S-enantiomer, Zoloft .

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is citalopram (orescitalopram).

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is paroxetine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is venlafaxine(racemic or an optical isomer).

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is desvenlafaxine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is duloxetine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is sibutramine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is milnacipran.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is mirtazapine.

In one embodiment, the one or more M₁R-selective antagonists istelenzepine (racemic or an optical isomer) and the one or moreantidepressants other than a M₁R-selective antagonist is bupropion.

In a related aspect, the invention provides methods for preparing or useof a medicament for treating one or more psychological conditions, themedicament containing a therapeutically effective amount of one or moreM₁R-selective antagonists. The medicament can optionally also containone or more antidepressants other than a M₁R-selective antagonist. Theembodiments for the medicament are as described herein.

In some embodiments, the methods and compositions of the inventioncomprise the combinations of pharmacological agents set forth herein. Insome embodiments, the methods and compositions of the invention consistessentially of the combinations of pharmacological agents set forthherein.

Definitions

The term “psychological disorder” or “psychological condition”interchangeably refer to a disorder of thought or emotion or a disorderof the brain that results in a disruption in a person's thinking,feeling, moods, and ability to relate to others. A psychologicaldisorder or condition can manifest as inappropriate or unprovokedexpressions of anger, sadness, fear, anxiety, or other sociopathicbehaviors, for example. Exemplified categories of psychologicaldisorders include, without limitation, affective disorders, anxietydisorders, cognitive disorders, impulse control disorders, substanceabuse/dependence disorders, attention deficit/hyperactivity disorders,eating disorders, movement disorders and sexual dysfunctions.Exemplified psychological conditions treatable by the present methodsand compositions include, without limitation, depression, anxiety,social anxiety disorder, agoraphobia, obsessive-compulsive disorder,post-traumatic stress disorder, body dysmorphic disorder, premenstrualdysphoric disorder and substance abuse/dependence. Psychologicaldisorders are described, for example, in Halgin and Whitbourne, AbnormalPsychology: Clinical Perspectives On Psychological Disorders, 4thEdition, 2005, McGraw-Hill College; Barlow and Antony, HandbookofAssessment and Treatment Planning for Psychological Disorders, 2002,Guilford Press; Claridge and Davis, Personality and PsychologicalDisorders, 2003, Oxford Univ Pr; and Clinical Handbook of psychologicalDisorders: A Step-by-Step Treatment Manual, Barlow, Ed., 2001, GuilfordPress. Diagnostic criteria for recognized psychological disorders can bemade with reference to Diagnostic and Statistical Manual of MentalDisorders (DSM IV, 2000, American Psychiatric Association).

The term “affective disorder” refers to any disorder of mood. Affectivedisorders include depression, mania, bipolar disorder, seasonalaffective disorder, anxiety, panic. See, for example, Paykel, Handbookof Affective Disorders, 1992, Longman Group Ltd.

The term “depression” refers to a clinical syndrome consistent with itsaccepted meaning in the art (see, for example, Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Text Revision[DSM-IV-TR]; American Psychiatric Association, 2000; AmericanPsychiatric Publishing, Inc., Arlington, Va.). Symptoms of depressioninclude, but are not limited to, persistent sadness, feelings ofpessimism, despair, feelings of helplessness, feelings of worthlessness,changes in moods, agitation, irritability, restlessness, loss ofinterest or pleasure in activities once enjoyed, thoughts of death orsuicide, inability to concentrate or make decisions, mental slowness,fatigue, decreased energy, insomnia or oversleeping, loss of appetite orovereating, weight loss or weight gain, persistent headaches ordigestive disorders, chronic pain, and abnormal hormonal circadianrhythms.

The term “substance dependence” is used in accordance with its commonlyunderstood meaning by those of skill in the art. For example, a clinicaldiagnosis of “substance dependence” according to the InternationalClassification of Diseases requires that three or more of the followingmust have been experienced or exhibited by the individual at some timeduring the previous year: (1) difficulties in controllingsubstance-taking behavior in terms of its onset, termination, or levelsof use; (2) a strong desire or sense of compulsion to take thesubstance; (3) progressive neglect of alternative pleasures or interestsbecause of psychoactive substance use, increased amount of timenecessary to obtain or take the substance or to recover from itseffects; (4) persisting with substance use despite clear evidence ofovertly harmful consequences, depressive mood states consequent to heavyuse, or drug related impairment of cognitive functioning; (5) evidenceof tolerance, such that increased doses of the psychoactive substanceare required in order to achieve effects originally produced by lowerdoses; (6) a physiological withdrawal state when substance use hasceased or been reduced, as evidence by: the characteristic withdrawalsyndrome for the substance; or use of the same (or a closely related)substance with the intention of relieving or avoiding withdrawalsymptoms. Further information regarding substance abuse can be found,for example, on the website for the National Institute on Drug Abuse(NIDA) at nida.nih.gov.

As used herein, “administering” means oral (“po”) administration,administration as a suppository, topical contact, intravenous (“iv”),intraperitoneal (“ip”), intramuscular (“im”), intralesional, intranasalor subcutaneous (“sc”) administration, or the implantation of aslow-release device e.g., a mini-osmotic pump, to a subject.Administration is by any route including parenteral and transmucosal(e.g., oral, nasal, vaginal, rectal, or transdermal). Parenteraladministration includes, e.g., intravenous, intramuscular,intra-arteriole, intradermal, subcutaneous, intraperitoneal,intraventricular, and intracranial. Other modes of delivery include, butare not limited to, the use of liposomal formulations, intravenousinfusion, transdermal patches, etc.

The terms “systemic administration” and “systemically administered”refer to a method of administering a compound or composition to a mammalso that the compound or composition is delivered to sites in the body,including the targeted site of pharmaceutical action, via thecirculatory system. Systemic administration includes, but is not limitedto, oral, intranasal, rectal and parenteral (i.e., other than throughthe alimentary tract, such as intramuscular, intravenous,intra-arterial, transdermal and subcutaneous) administration, with theproviso that, as used herein, systemic administration does not includedirect administration to the brain region by means other than via thecirculatory system, such as intrathecal injection and intracranialadministration.

The term “co-administer” refers to the simultaneous presence of twoactive agents in the blood of an individual. Active agents that areco-administered can be concurrently or sequentially delivered.

As used herein, the terms “treating” and “treatment” refer to delayingthe onset of, retarding or reversing the progress of, or alleviating orpreventing either the disease or condition to which the term applies, orone or more symptoms of such disease or condition.

As used herein, the terms “selective muscarinic receptor M₁ antagonist”and “M₁R-selective antagonist” refer to a muscarinic acetylcholinereceptor antagonist that exhibits preferential interaction with themuscarinic receptor M₁ subtype in comparison to the muscarinic receptorsubtypes M₂ and M₃. Exemplified M₁R-selective antagonists include, butare not limited to, pirenzepine and telenzepine. Preferential bindingneed not be complete. For example, despite comparable affinities for M₁and M₄ receptor subtypes, pirenzepine is classified as an M₁R-selectiveantagonist.

Preferential binding of a M₁R-selective antagonist can be measured in acompetitive displacement assay. A M₁R-selective antagonist willpreferentially displace a known M₁R-selective ligand (e.g. pirenzepineand/or telenzepine) in comparison to known M₂ (e.g. tripitramine,himbacine, methoctramine) and M₃ (e.g. darifenacin,hexahydrosiladiphenidol) selective ligands. Alternatively, aM₁R-selective antagonist will preferentially displace a nonselectivemuscarinic ligand (e.g., quinuclidinyl benzilate (QNB),N-methylscopolamine (NMS)) from an M₁ receptor subtype in comparison todisplacing the non-selective muscarinic ligand from binding to the M₂and M₃ receptor subtypes. The relative potencies for displacement ofradiolabeled competitors can be expressed in terms of the concentrationat which 50% of the competitor is displaced (IC₅₀), or in terms of anequilibrium dissociation constant (K_(d)). The IC₅₀ value and/or theequilibrium dissociation constant can be calculated using availablesoftware by entering the values of detected labeled ligand in thepresence of titrated amounts of unlabeled test compound (e.g., LIGAND(Munson, P. J., and Rodbard, D., Anal. Biochem. (1980) 107:220-39 orDATAPLOT, National Technical Information Services). A M₁R-selectiveantagonist will have an IC₅₀ value or a K_(d) value for binding to an M₁receptor subtype that is at least about 3-fold less, preferably at leastabout 10-fold less, and more preferably at least about 30-fold less thanits IC₅₀ value or K_(d) value for binding to M₂ and M₃ receptorsubtypes. Applicable radioligand binding assays, using radiolabeled NMSor QNB, are disclosed in Buckley, et al., Molecular Pharmacolog (1989)35:469-76 and Bolden, et al, J Pharmacol Exp Ther. (1992) 260:576-80.

As used herein, the phrase “consisting essentially of” refers to thegenera or species of active pharmaceutical agents included in a methodor composition, as well as any excipients inactive for the intendedpurpose of the methods or compositions. In some embodiments, the phrase“consisting essentially of” expressly excludes the inclusion of one ormore additional active agents other than a M₁R-selective antagonist andan antidepressant. In some embodiments, additional active agents thatcan be excluded include one or more of a prolactin inhibitor, aprolactin stimulator, a 5-HT receptor antagonist, a 5-HT receptoragonist, a NK-1 receptor antagonist and/or a dipeptidylpeptidase IVinhibitor.

The terms “controlled release,” “sustained release,” “extended release,”and “timed release” are intended to refer interchangeably to anydrug-containing formulation in which release of the drug is notimmediate, i.e., with a “controlled release” formulation, oraladministration does not result in immediate release of the drug into anabsorption pool. The terms are used interchangeably with “nonimmediaterelease” as defined in Remington: The Science and Practice of Pharmacy,21^(st) Ed., Lippencott Williams & Wilkins (2006). As discussed therein,immediate and nonimmediate release can be defined kinetically byreference to the following equation:

The “absorption pool” represents a solution of the drug administered ata particular absorption site, and k_(r), k_(a) and k_(e) are first-orderrate constants for (1) release of the drug from the formulation, (2)absorption, and (3) elimination, respectively. For immediate releasedosage forms, the rate constant for drug release k_(r) is far greaterthan the absorption rate constant k_(a). For controlled releaseformulations, the opposite is true, i.e., k_(r)<<k_(a), such that therate of release of drug from the dosage form is the rate-limiting stepin the delivery of the drug to the target area.

The terms “sustained release” and “extended release” are used in theirconventional sense to refer to a drug formulation that provides forgradual release of a drug over an extended period of time, for example,12 hours or more, and that preferably, although not necessarily, resultsin substantially steady-state blood levels of a drug over an extendedtime period.

As used herein, the term “delayed release” refers to a pharmaceuticalpreparation that passes through the stomach intact and dissolves in thesmall intestine.

As used herein, “synergy” or “synergistic” interchangeably refer to thecombined effects of two active agents that are greater than theiradditive effects. Synergy can also be achieved by producing anefficacious effect with combined inefficacious doses of two activeagents. The measure of synergy is independent of statisticalsignificance.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates the effect of pirenzepine (PZP) administeredintraperitoneally on immobility times of CD-1 mice subjected to the tailsuspension test. Male CD-1 mice (n=10 per group) were administeredpirenzepine as free base in doses of 5 mg/kg, 25 mg/kg or 50 mg/kg asdescribed in the Examples below. Control mice (VEH) were administered10% DMSO. * indicates p<0.05 vs. VEH.

FIG. 2 illustrates the effect of telenzepine (TZP) administeredintraperitoneally on immobility times of CD-1 mice subjected to the tailsuspension test. Male CD-1 mice (n=10 per group) were administeredtelenzepine as free base in doses of 5 mg/kg, 25 mg/kg or 50 mg/kg asdescribed in the Examples below. Control mice (VEH) were administered10% DMSO. * indicates p<0.05 vs. VEH. ** indicates p<0.001 vs. VEH.

FIG. 3 illustrates the effect of oral telenzepine (TZP) on immobilitytimes of CD-1 mice subjected to the tail suspension test. Male CD-1 mice(n=10 per group) were administered telenzepine as free base in doses of60 mg/kg, 80 mg/kg or 100 mg/kg as described in the Examples below.Control mice (VEH) were administered saline. * indicates p<0.05 vs. VEH.** indicates p<0.01 vs. VEH.

FIG. 4 illustrates the effect of combined administration of telenzepine(TZP) and sertraline (SRT) on immobility times of CD-I mice subjected tothe tail suspension test. Male CD-1 mice (n=10 per group) wereadministered intraperitoneally as free base telenzepine alone (5.0mg/kg), sertraline alone (1.0 mg/kg), or co-administered telenzepine(5.0 mg/kg) and sertraline (1.0 mg/kg) as described in the Examplesbelow. Control mice (VEH) were administered 10% DMSO. ** indicatesp<0.01 vs. VEH.

FIG. 5 illustrates the effect of combined administration of telenzepine(TZP) and venlafaxine (VEN) on immobility times of CD-I mice subjectedto the tail suspension test. Male CD-1 mice (n=10 per group) wereadministered intraperitoneally as free base telenzepine alone (5.0mg/kg), venlafaxine alone (10 mg/kg), or co-administered telenzepine(5.0 mg/kg) and venlafaxine (10 mg/kg) as described in the Examplesbelow. Control mice (VEH) were administered 10% DMSO. * indicates p<0.05vs. VEH. ** indicates p<0.01 vs. VEH. “aa” indicates p<0.01 vs. VEN. “b”indicates p<0.05 vs. TZP.

FIG. 6 illustrates the effect of combined administration of telenzepine(TZP) and fluoxetine (FLX) on immobility times of CD-I mice subjected tothe tail suspension test. Male CD-1 mice (n=10 per group) wereadministered intraperitoneally as free base telenzepine alone (10mg/kg), fluoxetine alone (4 mg/kg), or co-administered telenzepine (10mg/kg) and fluoxetine (4 mg/kg) as described in the Examples below.Control mice (VEH) were administered 10% DMSO. ** indicates p<0.01 vs.VEH.

DETAILED DESCRIPTION 1. Introduction

As discussed above, earlier studies in rats and mice demonstrated thatpirenzepine administered systemically failed to elicit any behavioraleffects (see, Rogoz, Z., Skuza, G., Sowinska, H., Pol. J. Pharmacol.Pharm., 1981, vol. 31, pp. 615-26), and that pirenzepine does notexhibit significant penetration of the blood-brain barrier in variousspecies, including rodents and humans (see, Hammer, R., Koss, F. W.,Scand. J. Gastroenterol., Suppl., 1979, vol. 14, no. 57, pp. 1-6;Bymaster, F. P., et al., J. Pharmacol. Exp. Ther., 1993, vol. 267, no.1, pp. 16-24). Surprisingly, contrary to the published literature, thecurrent invention demonstrates that M₁R-selective antagonists, includingpirenzepine and telenzepine, can cross the blood-brain barrier intherapeutic amounts and therefore have useful antidepressant activitywhen administered systemically. These agents also are useful fortreating other psychological conditions often treated withantidepressants.

The present invention also demonstrates that the use of M₁R-selectiveantagonists in combination with certain other therapeutic agentsproduces unexpected synergistic effects that are advantageous fortreating psychological conditions, including depression.

The present invention provides an efficacious pharmacological treatmentfor depression, anxiety, social anxiety disorder, agoraphobia,obsessive-compulsive disorder, post-traumatic stress disorder, bodydysmorphic disorder, premenstrual dysphoric disorder and substance abuseor dependence (e.g., nicotine, alcohol, sedatives, etc. ). Systemicadministration of a selective muscarinic receptor M₁ (M₁R-selective)antagonist unexpectedly provides antidepressant effects. Surprisingly,therapeutically effective amounts of one or more M₁R-selectiveantagonists efficacious in treating psychological disorders, includingdepression, can cross the blood-brain barrier when systemicallyadministered to a subject. In addition, co-administration of one or moreM₁R-selective antagonists and one or more antidepressant agents otherthan a M₁R-selective antagonist unexpectedly provides for greaterantidepressant effects than is accomplished by administering any ofthese categories of drug alone.

2. Methods of Treating Psychological Disorders

a. Conditions Subject to Treatment

The present methods and compositions find use in the treatment ofpsychological disorders. Exemplified general categories of psychologicaldisorders treatable by the present methods and compositions include,without limitation, (1) affective, anxiety and impulse control disorders(including pathological overeating), (2) substance abuse/dependencedisorders (i.e., addictive behaviors), (3) cognitive, attention deficitand hyperactivity disorders, (4) movement disorders and sexualdysfunctions, and (5) eating disorders (e.g., anorexia nervosa andbulimia nervosa).

The action of acetylcholine on muscarinic receptors in the centralnervous system influences a diverse array of behaviors, includingcognition, insight, vigilance, affect, sensory-motor gating and bothreflexive and directed motility (Bymaster et al., Curr Drug Targets CNSNeurol Disord (2002) 1:163-181). Muscarinic receptors influence thesefunctions not only through interactions with cholinergic neurons, butalso through modulation of the activity of forebrain/midbraindopaminergic, GABAergic and glutamatergic neurons. Neurolocalization andmicrodialysis studies have confirmed the influence muscarinic receptorsand their agonists or antagonists have over these systems, with thedirectionality of modulation (excitation/inhibition) dependent on thespecific receptor subtype. Specifically, local microinjection of theM₁/M₄ preferring antagonist, pirenzepine, results in decreased dopamineefflux in the striatum (Smolders et al., J Neurochem (1997)68:1942-1948). Similarly, when directly injected into the midbrain, theM₁/M₄ receptor preferring antagonist, telenzepine, produces reduced GABAefflux (Smolders et al., 1997, supra). Likewise, non-subtype selectiveantagonists, such as scopolamine, produce elevated acetylcholine levelsin the forebrain (Izurieta-Sanchez et al., Eur J Pharmacol (2000)399:151-160).

With regard to substance abuse and disorders of dependence, mesolimbicdopamine circuits are thought to play important roles in the formationand perpetuation of addictive behavior (Berridge and Robinson, Brain ResBrain Res Rev (1998) 28:309-369; Crespo et al., J Neurosci (2006)26:6004-6010; Di Chiara and Imperato, Proc Natl Acad Sci USA (1988)85:5274-5278; Hernandez and Hoebel, Life Sci (1988) 42:1705-1712).Studies with rodents have shown that a specific structure in thestriatum, the nucleus accumbens (NAc), is involved in the regulation ofreward and aversion. The NAc lies in the medioventral striatum and canbe further dissected into shell, core and rostral pole subterritories(Zahm and Brog, Neuroscience (1992) 50:751-767).

Rats will self-administer dopamine agonists into the NAc (Hoebel et al.,Psychopharmacology (Berl) (1983) 81:158-163) and a large number of drugsthat are known to provoke abuse and habituation in humans have beenshown to increase extracellular dopamine levels in the NAc (Di Chiaraand Imperato, 1988, supra; Hernandez and Hoebel, 1988, supra; Rada etal., Pharmacol Biochem Behav (1996) 53:809-816). Conversely, decreasedextracellular dopamine in the nucleus accumbens has been observed toaccompany aversion during morphine-induced and nicotine-inducedwithdrawal (Acquas and Di Chiara, (1992) J Neurochem 58:1620-1625; Dianaet al., J Pharmacol Exp Ther (1995) 272:781-785; Pothos et al., BrainRes (1991) 566:348-350; Rada et al., Psychopharmacology (Berl) (2001)157:105-110). The effects of dopamine appear to be mediated by receptorsubtypes D1 and D2. Injection of dopamine D1 or D2 agonists into the NAcshell but not core, has been shown to reinstate drug-seeking behavior inrats that have been operantly conditioned to press levers for cocaine,but then have had the behavior extinguished by substituting saline forcocaine (Schmidt et al., Eur J Neurosci (2006) 23:219-228).

Within the NAc cholinergic and dopaminergic circuits appear to bepharmacologically opposed. Local intra-accumbal administration of eitheratropine (a nonspecific muscarinic antagonist) or mecamylamine (anonspecific nicotinic antagonist) has been reported to block theacquisition of opiate reinforcement (Crespo et al., 2006, supra),whereas morphine decreases acetylcholine levels in the NAc (Fiserova etal., Psychopharmacology (Berl) (1999) 142:85-94; Rada et al.,Neuropharmacology (1991) 30:1133-1136) and naloxone-induced opiatewithdrawal increases acetylcholine levels (Fiserova et al., 1999, supra;Rada et al., 1991 supra; Rada et al., 1996, supra). Similar phenomenahave been observed in conjunction with mecamylamine-induced withdrawalin nicotine-dependent rats (Rada et al., 2001, supra). In support of abroad general connection between elevated ACh and dysphoric states, AChis released in the NAc by a conditioned aversive taste (Mark et al.,Brain Res (1995) 688:184-188), aversive brain stimulation (Rada andHoebel, Brain Res (2001) 888:60-65), and withdrawal from diazepam (Radaand Hoebel, Eur J Pharmacol (2005) 508:131-138), alcohol (Rada et al.,Pharmacol Biochem Behav (2004) 79:599-605) or sugar (Colantuoni et al.,Obes Res (2002) 10, 478-488). Attenuation of cholinergic transmission isthus a therapeutically attractive approach to the treatment of disordersof addiction and habituation. Such disorders need not be purelypharmacologic as the findings with sucrose withdrawal exemplify.

Accordingly, neuropsychiatric applications for compounds that possessthe ability to preferentially modulate M₁ muscarinic receptors arewidespread. Therefore, the present methods find use in treating avariety of conditions, including those resulting from impaired: i)cognitive processing, ii) affective processing, and/or iii) appetitivemotivation. Conditions within these categories include (1) affective,anxiety and impulse control disorders (including pathologicalovereating), (2) substance abuse/dependence disorders (i.e., addictivebehaviors), (3) cognitive, attention deficit and hyperactivitydisorders, (4) movement disorders and sexual dysfunctions, and (5)eating disorders (e.g., anorexia nervosa and bulimia nervosa).

Exemplified affective, anxiety and impulse control disorders includeaffective disorders (including but not limited to depression, bipolardisorder, dysthymic disorder, premenstrual dysphoric disorder), anxietydisorders (including but not limited to generalized anxiety disorder,social anxiety disorder, panic disorder, post-traumatic stress disorder,obsessive compulsive disorder, agoraphobia, specific phobias, conversiondisorders, body dysmorphic disorder), and impulse control disorders(including but not limited to kleptomania, pyromania, trichotillomania,pathological gambling, pathological overeating).

Exemplified substance abuse and/or dependence disorders include physicaland/or psychological dependence on pharmacological agents, including butnot limited to nicotine, alcohol, opioids, psychostimulants,sedatives/hypnotics. The term “opioids” includes, without limitation,natural, semisynthetic and unnatural agonists or partial agonists ofopioid receptors. The term “psychostimulants” includes, withoutlimitation, antagonists of the dopamine reuptake transporter and/oragents which directly promote dopamine release and comprise withoutlimitation, cocaine, synthetic dopamine transporter inhibitors,amphetamines, phenmetrazine and methylenedioxyamphetamines.

Exemplified cognitive, attention deficit and hyperactivity disordersinclude cognitive disorders/dysfunction (including but not limited toschizophrenia, Alzheimer's disease, mild cognitive impairment,dementias), and attention deficit/hyperactivity disorder (e.g., ADD,ADHD).

Exemplified movement disorders include but are not limited to thosesecondary to Parkinson's disease, Huntington's disease, dyskinesias,dystonias, and tremors. Exemplified sexual dysfunctions include but arenot limited to premature ejaculation and arousal disorder.

Exemplified eating disorders include but are not limited to anorexianervosa and bulimia nervosa.

b. Pharmacological Agents

The pharmacological agents used in the present methods and compositionsinclude the one or more active agents, described in detail below, in anypharmaceutically acceptable form, including any pharmaceuticallyacceptable salts, prodrugs, racemic mixtures, conformational and/oroptical isomers, crystalline polymorphs and isotopic variants of the oneor more pharmacological agents.

i. Selective Muscarinic Receptor M₁ Antagonists

The present methods treat psychological conditions, includingdepression, by administering to an individual in need thereof atherapeutic amount of one or more selective muscarinic receptor M₁antagonists. Muscarinic antagonists are generally reviewed in Chapter 7of Goodman and Gilman's The Pharmacological Basis of Therapeutics,supra, hereby incorporated herein by reference. Exemplified selectivemuscarinic receptor M₁ antagonists include pirenzepine and telenzepine,the structures of which are shown below.

Pirenzepine(5,11-Dihydro-11-[(4-methyl-1-piperazinyl)acetyl]-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one)is manufactured and sold as pirenzepine dihydrochloride by severalpharmaceutical companies, including Azupharma (Stuttgart, Germany),Boehringer Ingelheim (Ingelheim, Germany; sold as Gastrozepin®),Dolorgiet (Bonn, Germany). Pirenzepine can be administered in doses fromabout 50 mg/day to about 200 mg/day, for example, about 100-150 mg/day,or 50, 100, 150, or 200 mg/day. Alternatively, pirenzepine can beadministered in doses of about 0.1 mg/kg/day to about 10 mg/kg/day,usually from about 0.7 mg/kg/day to about 5 mg/kg/day. Analogs ofpirenzepine also find use in carrying out the present methods. Chemicalanalogs of pirenzepine are disclosed, for example, in U.S. Pat. Nos.3,660,380; 3,743,734; and 5,324,832, the disclosures of each of whichare hereby incorporated herein by reference in their entirety for allpurposes.

Telenzepine(4,9-Dihydro-3-methyl-4-[(4-methyl-1-piperazinyl)acetyl]-10H-thieno[3,4-b][1,5]benzodiazepin-10-one)is commercially available from, for example, Tocris Bioscience(Ellisville, Mo.) and Sigma-Aldrich, Inc. (St. Louis, Mo.) astelenzepine dihydrochloride. Further, the synthesis of telenzepine isdisclosed in U.S. Pat. No. 4,381,301, hereby incorporated herein byreference. Telenzepine can be administered in doses from about 0.5 mgper day to about 10 mg per day, for example, about 1-5 mg/day, or 0.5,1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 mg/day. Analogs of telenzepine also finduse in carrying out the present methods. Chemical analogs andenantiomers of telenzepine are disclosed, for example, in U.S. Pat. Nos.3,953,430; 4,168,269; 4,172,831; 4,381,301; 5,140,025 and 5,324,832, thedisclosures of each of which are hereby incorporated herein by referencein their entirety for all purposes.

In some embodiments a racemic preparation of telenzepine containing amixture of (+) and (−) enantiomers is administered. In some embodiments,the (+) or (−) enantiomer of telenzepine is administered. Telenzepineexists in two chirally distinct states separated by an activationbarrier of 35.5 kcal/mol (Eveleigh et al., Mol Pharmacol (1989)35:477-483; and Schudt et al., Eur J Pharmacol (1989) 165:87-96). The(+) form of telenzepine has potent antimuscarinic activity whereas the(−) form is considerably less active. The selectivity of telenzepineappears to vary at different anatomic sites with the (+) form moreeffective on cortical receptors by a factor of 400 compared to the (−)isomer; on cardiac receptors the selectivity is less and the (+) form ismore potent than the (−) form by a factor of 50 (Eveleigh et al.,supra). The two forms interconvert slowly and with a half time ofapproximately 200 hours at 90 degrees (Eveleigh et al., supra). Multiplestudies have affirmed that the two forms have distinct activities(Eltze, Eur J Pharmacol (1990) 180:161-168; Eveleigh et al., supra;Feifel et al., Eur J Pharmacol (1991) 195:115-123; Kilian et al., AgentsActions Suppl 34:131-147; Schudt et al., supra).

ii. Anti-Depressants

Antidepressant agents that are not M₁R-selective antagonists for use inthe present invention are not limited by their mechanism of action andany class of antidepressant is applicable. For instance, tricyclicantidepressants (TCAs) and analogs thereof, serotonin reuptakeinhibitors, monoamine oxidase inhibitors (MAOIs), serotonin agonists andprodrugs thereof, norepinephrine reuptake inhibitors, dopamine reuptakeinhibitors, and serotonin reuptake accelerators can all be administeredin combination with one or more M₁R-selective antagonists. Serotoninreuptake inhibitors include both selective serotonin reuptake inhibitors(SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs).Norepinephrine reuptake inhibitors include both the specificnorepinephrine reuptake inhibitors as well as the mixednorepinephrine-dopamine reuptake inhibitors (NDRIs).Serotonin-norepinephrine-dopamine, or “triple reuptake inhibitors” alsofind use in the present invention. Other categories of antidepressantcan also be used, for example, the tetracyclic antidepressantsmaprotiline or mianserin, or the agents trazodone, nefazodone, orbuspirone; corticotropin releasing factor receptor 1 (CRF1) antagonists,and compounds discovered to have activity in the setting of psychosis orbipolar disorder, including amoxapine, clozapine, risperidone,olanzapine, quetiapine and aripiprazole.

Tricyclic antidepressants for use in the present invention includeamineptine, amitriptyline, clomipramine, desipramine, doxepin,dothiepin, imipramine, nortriptyline, protriptyline, trimipramine,amoxapine and the muscle relaxant cyclobenzaprine. Other unlistedtricyclic antidepressants and analogs thereof can also be used.

In one embodiment, an effective amount of one or more M₁R-selectiveantagonists is co-administered with an effective amount of a selectiveserotonin reuptake inhibitor. Exemplary selective serotonin reuptakeinhibitors include citalopram, escitalopram, fluoxetine (racemic or anoptical isomer), fluvoxamine, paroxetine and sertraline (and itsS-enantiomer, Zoloft®), although SSRIs not listed are applicable. In oneembodiment, citalopram (or escitalopram) is co-administered with one ormore M₁R-selective antagonists. In one embodiment, an effective amountof fluoxetine (racemic or an optical isomer) is co-administered. In oneembodiment, an effective amount of fluvoxamine is co-administered. Inone embodiment, an effective amount of sertraline (or its S-enantiomer,Zoloft®) is co-administered. In one embodiment, an effective amount ofparoxetine is co-administered. In one embodiment, an effective amount ofduloxetine is co-administered.

In one embodiment, an effective amount of one or moreserotonin-norepinephrine reuptake inhibitors are co-administered withone or more M₁R-selective antagonist. Exemplary serotonin-norepinephrinereuptake inhibitors include milnacipran, mirtazapine, venlafaxine(racemic or an optical isomer), duloxetine,(−)1-(1-dimethylaminomethyl-5-methoxybenzo-cyclobutan-1-yl) cyclohexanol(S33005), DVS-233 (desvenlafaxine), DVS-233 SR and sibutramine, althoughSNRIs not listed are also of use. Although the mechanism of action ofmirtazapine may differ from that of other SNRIs, owing to its apparentdual serotonergic and noradrenergic action, it is considered herein as amember of the SNRI class of antidepressants. In one embodiment, aneffective amount of venlafaxine (racemic or an optical isomer) isco-administered. In one embodiment, an effective amount ofdesvenlafaxine is co-administered. In one embodiment, an effectiveamount of sibutramine is co-administered. In one embodiment, aneffective amount of duloxetine is co-administered. In one embodiment, aneffective amount of milnacipran is co-administered. In one embodiment,an effective amount of mirtazapine is co-administered.

In other embodiments, an effective amount of one or more selectivenorepinephrine reuptake inhibitors is co-administered with one or moreM₁R-selective antagonists. Exemplary selective norepinephrine reuptakeinhibitors include reboxetine and atomoxetine.

In one embodiment, an effective amount of one or morenorepinephrine-dopamine reuptake inhibitors are co-administered with oneor more M₁R-selective antagonists. Exemplary norepinephrine-dopaminereuptake inhibitors include amineptine, modafinil, GW353162 andbupropion. In the case of bupropion, metabolites are thought to beresponsible for the noradrenergic reuptake blockade. In one embodiment,an effective amount of bupropion is co-administered.

In one embodiment, an effective amount of one or more triple(serotonin-norepinephrine-dopamine) reuptake inhibitors areco-administered with one or more M₁R-selective antagonist. Exemplarytriple reuptake inhibitors include indatraline, SEP-225289, DOV 216,303and (+)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride(DOV 21,947).

Monoamine oxidase inhibitors for use in the present invention includebefloxatone, brofaromine, deprenyl, isocarboxazid, moclobemide,pargyline, phenelzine, selegiline and tranylcypromine, together withtheir sustained delivery and transdermal delivery forms.

Antidepressants that can be co-administered with an M₁R-selectiveantagonist include maprotiline, tianeptine, nefazodone and trazodone.

Appropriate dosages for antidepressants will depend on the chosen routeof administration and formulation of the composition, among otherfactors. For instance, tricyclic antidepressants are administered at adose of about 25 to about 600 mg/day, and usually at a dose of about 75to about 300 mg/day.

Serotonin-reuptake inhibitors are administered at a dose of about 5 toabout 400 mg/day, and usually administered at about 20 to about 250mg/day. In particular, in practicing the present methods, venlafaxine(racemic or an optical isomer) can be administered at about 9 mg toabout 225 mg per dose, and is usually administered at about 37.5 mg, 75mg, 150 mg or 225 mg per dose. Venlafaxine is typically administered atabout 25-550 mg/day and usually at about 37.5-375 mg/day, more typicallyabout 75-225 mg/day, and most typically at about 37.5, 75, 150, 225, or300 mg/day. As appropriate for an individual patient, daily venlafaxinedosages can be divided and administered one time, two times, threetimes, four or more times a day. Desvenlafaxine can be administered at adose of about 50-600 mg/day, for example, about 50, 100, 200, 400 or 600mg/day. Sertraline (or its S-enantiomer, Zoloft®) can be administered indoses ranging from about 50-200 mg/day, usually about 100-150 mg/day.Fluoxetine (racemic or an optical isomer) can be administered in dosesranging from about 5-50 mg/day, usually about 20-40 mg/day. Fluvoxaminecan be administered in doses ranging from about 50-300 mg/day, usuallyabout 100-200 mg/day. Paroxetine can be administered in doses rangingfrom about 10-50 mg/day, usually about 20-40 mg/day.

In carrying out the present methods, citalopram (or escitalopram) can beadministered at about 5-60 mg/day, and preferably at about 10, 20 or 30mg/day. Usually, citalopram is administered once a day, for instance inthe morning or in the evening. However, some patients are given dosagesof citalopram two or more times a day. Mirtazapine can be administeredat a dose of about 5-100 mg/day, for example, about 7.5, 15, 30, 45 or90 mg/day. Milnacipran can be administered at a dose of about 25-200mg/day, for example, about 25, 50, 100, 150 or 200 mg/day.

Atypical antidepressants, including bupropion, nefazodone and trazodoneare administered at a dose of about 50-600 mg/day, and usually at about150-400 mg/day. Bupropion can be administered at a dose of about 25-300mg/day, for example, about 25, 50, 100, 150, 200, 300 mg/day. Monoamineoxidase inhibitors are typically administered at a dose of about 5-90mg/day, and usually at about 10-60 mg/day.

iii. Combinations of Pharmacological Agents

In some embodiments, the one or more M₁R-selective antagonists areco-administered or co-formulated with and one or more antidepressantsthat are not a M₁R-selective antagonist. The M₁R-selective antagonistsand antidepressants are as described above.

In some embodiments, the one or more M₁R-selective antagonists areco-administered or co-formulated with and one or more 5-HT2c receptoragonists. Exemplified 5-HT2c receptor agonists include1-(m-chlorophenyl)piperazine (m-CPP), mirtazapine, APD-356 (lorcaserin),SCA-136 (vabicaserin), ORG-12962, ORG-37684, ORG-36262, ORG-8484,Ro-60-175, Ro-60-0332, VER-3323, VER-5593, VER-5384, VER-8775,LY-448100, WAY-161503, WAY-470, WAY-163909, MK-212, BVT. 933, YM-348,IL-639, IK-264, ATH-88651, ATHX-105 and the like (see, e.g., Nilsson BM,J. Med. Chem. 2006, 49:4023-4034).

In some embodiments, the one or more M₁R-selective antagonists areco-administered or co-formulated with m-CPP. In some embodiments, theone or more M₁R-selective antagonists are co-administered orco-formulated with mirtazapine. In some embodiments, the one or moreM₁R-selective antagonists are co-administered or co-formulated withlorcaserin. In some embodiments, the one or more M₁R-selectiveantagonists are co-administered or co-formulated with Ro-60-175. In someembodiments, the one or more M₁R-selective antagonists areco-administered or co-formulated with Ro-60-0332.

In some embodiments, a combination of one or more M₁R-selectiveantagonists, one or more antidepressants that are not a M₁R-selectiveantagonist, and one or more 5-HT2c receptor agonists is administered.

iv. Isomers

All conformational isomers (e.g., cis and trans isomers) and all opticalisomers (e.g., enantiomers and diastereomers), racemic, diastereomericand other mixtures of such isomers, as well as solvates, hydrates,isomorphs, polymorphs and tautomers of the therapeutic agents are withinthe scope of the present invention.

v. Isotopes

The present invention also includes isotopically-labeled variants of thetherapeutic agents, wherein one or more atoms are replaced by one ormore atoms having specific atomic mass or mass numbers.Isotopically-labeled variants of the therapeutic agents and prodrugsthereof, as well as isotopically-labeled, pharmaceutically acceptablesalts of the therapeutic agents and prodrugs thereof, are within thescope of the present invention. In certain circumstances substitutionwith heavier isotopes, such as deuterium (²H), can provide increasedmetabolic stability, which offers therapeutic advantages such asincreased in vivo half-life or reduced dosage requirements.Isotopically-labeled variants of the therapeutic agents of thisinvention and prodrugs thereof can generally be prepared according tomethods known to those skilled in the art by substituting anisotopically-labeled reagent for a non-isotopically labeled reagent.

c. Administration

i. Duration of Administration

Usually, the one or more M₁R-selective antagonists are administered tothe individual over an extended period of time. The methods can becarried out for at least 20 days, in some embodiments for at least 40,60, 80 or 100 days, and in some embodiments for at least 150, 200, 250,300, 350 days, 1 year or longer. Certain individuals receive the presenttreatment methods for longer than a year, for example, at least 400,450, 500, 550, 600, 650, 700, 800, 900, 1000 days. However, individualscan be successfully treated with the present methods for 2 years, 3years, 4 years or longer.

ii. Scheduling

Generally, in practicing the present methods, effective amounts of oneor more M₁R-selective antagonists co-administered with one or moreantidepressants can be administered together or separately,simultaneously or at different times. The M₁R-selective antagonists andantidepressants independently can be administered once, twice, three,four times daily or more or less often, as needed. Preferably, the oneor more M₁R-selective antagonists and the one or more antidepressantsare administered once daily. Preferably, the one or more M₁R-selectiveantagonists and the one or more antidepressants are administered at thesame time or times, for instance as an admixture. The one or moreM₁R-selective antagonists and one or more antidepressants can beadministered in a sustained-release formulation.

For certain patients, the methods are carried out concurrentlyadministering the one or more M₁R-selective antagonists and then the oneor more antidepressants from the initiation of treatment. For certainpatients, the methods are carried out by first administering the one ormore M₁R-selective antagonists, and then subsequently co-administeringthe one or more antidepressants. The patient initially can be given theone or more M₁R-selective antagonists alone for as long as 3 days, 5days, 7 days, 10 days, 14 days, 20 days, or 30 days before commencingadministration of one or more antidepressants.

The one or more M₁R-selective antagonists can be administeredprophylactically to prevent symptoms of a psychological conditions in asubject at risk, or therapeutically to ameliorate symptoms of thepsychological condition for a sustained period of time.

iii. Routes of Administration

As such, administration of one or more M₁R-selective antagonists, aloneor in combination with one or more antidepressants, can be achieved invarious ways, including oral, buccal, parenteral, including intravenous,intradermal, subcutaneous, intramuscular, transdermal, transmucosal,intranasal, etc., administration. The one or more M₁R-selectiveantagonists can be administered by the same or different route ofadministration when co-administered with one or more antidepressants.

In some embodiments, one or more M₁R-selective antagonists, alone or incombination, can be administered in a local rather than systemic manner,for example, in a depot or sustained release formulation.

iv. Methods of Determining Appropriate Dosages

Administered dosages for M₁R-selective antagonists and antidepressantsare in accordance with dosages and scheduling regimens practiced bythose of skill in the art. General guidance for appropriate dosages ofall pharmacological agents used in the present methods is provided inGoodman and Gilman's The Pharmacological Basis of Therapeutics, 11thEdition, 2006, supra, and in a Physicians' Desk Reference (PDR), forexample, in the 59^(th) (2005) or 60^(th) (2006) Eds., Thomson PDR, eachof which is hereby incorporated herein by reference. Published dosagesfor M₁R-selective antagonists are for indications distinct fromtreatments to ameliorate depression or other psychological conditions.In the compositions and methods of the present invention, efficaciousdosages of M₁R-selective antagonists and antidepressants for practicingthe present invention can be equal to or less than (e.g., about 25, 50,75 or 100%) the dosages published for other indications.

The appropriate dosage of one or more M₁R-selective antagonists andantidepressants will vary according to several factors, including thechosen route of administration, the formulation of the composition,patient response, the severity of the condition, the subject's weight,and the judgment of the prescribing physician. The dosage can beincreased or decreased over time, as required by an individual patient.Usually, a patient initially is given a low dose, which is thenincreased to an efficacious dosage tolerable to the patient.

Determination of an effective amount is well within the capability ofthose skilled in the art, especially in light of the detailed disclosureprovided herein. Generally, an efficacious or effective amount of acombination of one or more M₁R-selective antagonists and one or moreantidepressants is determined by first administering a low dose or smallamount of an M₁R-selective antagonist alone, and then incrementallyincreasing the administered dose or dosages, adding a second or thirdmedication as needed, until a desired effect of is observed in thetreated subject with minimal or no toxic side effects. Applicablemethods for determining an appropriate dose and dosing schedule foradministration of a combination of the present invention are described,for example, in Goodman and Gilman's The Pharmacological Basis ofTherapeutics, 11th Edition, 2006, supra; in a Physicians' Desk Reference(PDR), supra; in Remington: The Science and Practice of Pharmacy,21^(st) Ed., 2006, supra; and in Martindale: The Complete DrugReference, Sweetman, 2005, London: Pharmaceutical Press., and inMartindale, Martindale: The Extra Pharmacopoeia, 31st Edition., 1996,Amer Pharmaceutical Assn, each of which are hereby incorporated hereinby reference.

Dosage amount and interval can be adjusted individually to provideplasma levels of the active compounds which are sufficient to maintaintherapeutic effect. Preferably, therapeutically effective serum levelswill be achieved by administering single daily doses, but efficaciousmultiple daily dose schedules are included in the invention. In cases oflocal administration or selective uptake, the effective localconcentration of the drug may not be related to plasma concentration.One having skill in the art will be able to optimize therapeuticallyeffective local dosages without undue experimentation.

3. Pharmaceutical Compositions

The present invention further provides pharmaceutical compositionscomprising a mixture of a therapeutically effective amount of one ormore M₁R-selective antagonists and one or more antidepressants. In someembodiments, the M₁R-selective antagonists are selected from the groupconsisting of telenzepine, pirenzepine and mixtures thereof.

In certain embodiments, the pharmaceutical compositions comprise one ormore antidepressants that are a selective serotonin reuptake inhibitor(SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI), anorepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, anorepinephrine-dopamine reuptake inhibitor (NDRI), aserotonin-norepinephrine-dopamine reuptake inhibitor, a serotoninreuptake accelerator, a serotonin agonist and prodrugs thereof. In oneembodiment, the pharmaceutical composition comprises one or moreantidepressants selected from the group consisting of venlafaxine(racemic or an optical isomer), duloxetine, fluoxetine (racemic or anoptical isomer), citalopram, escitalopram, fluvoxamine, paroxetine,S33005, DVS-233 (desvenlafaxine), DVS-233 SR, bupropion, GW353162,sibutramine, atomoxetine and sertraline (or its S-enantiomer, Zoloft®).

In one embodiment, the pharmaceutical composition comprisestherapeutically effective amounts of telenzepine or pirenzepine and anSSRI. In one embodiment, the pharmaceutical composition comprisestherapeutically effective amounts of telenzepine or pirenzepine andcitalopram (or escitalopram). In one embodiment, the pharmaceuticalcomposition comprises therapeutically effective amounts of telenzepineor pirenzepine and sertraline (or its S-enantiomer, Zoloft®). In oneembodiment, the pharmaceutical composition comprises therapeuticallyeffective amounts of telenzepine or pirenzepine and fluoxetine (racemicor an optical isomer). In one embodiment, the pharmaceutical compositioncomprises therapeutically effective amounts of telenzepine orpirenzepine and fluvoxamine. In one embodiment, the pharmaceuticalcomposition comprises therapeutically effective amounts of telenzepineor pirenzepine and paroxetine.

In one embodiment, the pharmaceutical composition comprisestherapeutically effective amounts of telenzepine or pirenzepine and anSNRI. In one embodiment, the pharmaceutical composition comprisestherapeutically effective amounts of telenzepine or pirenzepine andvenlafaxine (racemic or an optical isomer). In one embodiment, thepharmaceutical composition comprises therapeutically effective amountsof telenzepine or pirenzepine and desvenlafaxine. In one embodiment, thepharmaceutical composition comprises therapeutically effective amountsof telenzepine or pirenzepine and duloxetine. In one embodiment, thepharmaceutical composition comprises therapeutically effective amountsof telenzepine or pirenzepine and milnacipran. In one embodiment, thepharmaceutical composition comprises therapeutically effective amountsof telenzepine or pirenzepine and mirtazapine.

In one embodiment, the pharmaceutical composition comprisestherapeutically effective amounts of telenzepine or pirenzepine andbupropion.

A combination of one or more M₁R-selective antagonists and one or moreantidepressants can be administered to a subject, e.g., a human patient,a domestic animal such as a cat or a dog, independently or together inthe form of their pharmaceutically acceptable salts, or in the form of apharmaceutical composition where the compounds are mixed with suitablecarriers or excipient(s) in a therapeutically effective amount, e.g., atdoses effective to effect desired result of reducing the symptoms of thepsychological condition.

An M₁R-selective antagonist-antidepressant combination of this inventioncan be incorporated into a variety of formulations for therapeuticadministration. More particularly, a combination of the presentinvention can be formulated into pharmaceutical compositions, togetheror separately, by formulation with appropriate pharmaceuticallyacceptable carriers or diluents, and can be formulated into preparationsin solid, semi-solid, liquid or gaseous forms, such as tablets,capsules, pills, powders, granules, dragees, gels, slurries, ointments,solutions, suppositories, injections, inhalants and aerosols.

Suitable formulations for use in the present invention are found in, forexample, in Remington: The Science and Practice of Pharmacy, 21^(st)Ed., 2006, supra; Martindale: The Complete Drug Reference, Sweetman,2005, London: Pharmaceutical Press.; Niazi, Handbook of PharmaceuticalManufacturing Formulations, 2004, CRC Press; and Gibson, PharmaceuticalPreformulation and Formulation: A Practical Guidefrom Candidate DrugSelection to Commercial Dosage Form, 2001, Interpharm Press, which arehereby incorporated herein by reference. The pharmaceutical compositionsdescribed herein can be manufactured in a manner that is known to thoseof skill in the art, i.e., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes. The following methods andexcipients are merely exemplary and are in no way limiting.

In one embodiment, an M₁R-selective antagonist-antidepressantcombination is prepared for delivery in a sustained-release, controlledrelease, extended-release, timed-release or delayed-release formulation,for example, in semi-permeable matrices of solid hydrophobic polymerscontaining the therapeutic agent. Various types of sustained-releasematerials have been established and are well known by those skilled inthe art. Current extended-release formulations include film-coatedtablets, multiparticulate or pellet systems, matrix technologies usinghydrophilic or lipophilic materials and wax-based tablets withpore-forming excipients (see, for example, Huang, et al. Drug Dev. Ind.Pharm. 29:79 (2003); Pearnchob, et al. Drug Dev. Ind. Pharm. 29:925(2003); Maggi, et al. Eur. J. Pharm. Biopharm. 55:99 (2003); Khanvilkar,et al., Drug Dev. Ind. Pharm. 228:601 (2002); and Schmidt, et al., Int.J. Pharm. 216:9 (2001)). Sustained-release delivery systems can,depending on their design, release the compounds over the course ofhours or days, for instance, over 4, 6, 8, 10, 12, 16, 20, 24 hours ormore. Usually, sustained release formulations can be prepared usingnaturally-occurring or synthetic polymers, for instance, polymeric vinylpyrrolidones, such as polyvinyl pyrrolidone (PVP); carboxyvinylhydrophilic polymers; hydrophobic and/or hydrophilic hydrocolloids, suchas methylcellulose, ethylcellulose, hydroxypropylcellulose, andhydroxypropylmethylcellulose; and carboxypolymethylene.

The sustained or extended-release formulations can also be preparedusing natural ingredients, such as minerals, including titanium dioxide,silicon dioxide, zinc oxide, and clay (see, U.S. Pat. No. 6,638,521,herein incorporated by reference). Exemplified extended releaseformulations that can be used in delivering an M₁R-selectiveantagonist-antidepressant combination of the present invention includethose described in U.S. Pat. Nos. 6,635,680; 6,624,200; 6,613,361;6,613,358, 6,596,308; 6,589,563; 6,562,375; 6,548,084; 6,541,020;6,537,579; 6,528,080 and 6,524,621, each of which is hereby incorporatedherein by reference. Controlled release formulations of particularinterest include those described in U.S. Pat. Nos. 6,607,751; 6,599,529;6,569,463; 6,565,883; 6,482,440; 6,403,597; 6,319,919; 6,150,354;6,080,736; 5,672,356; 5,472,704; 5,445,829; 5,312,817 and 5,296,483,each of which is hereby incorporated herein by reference. Those skilledin the art will readily recognize other applicable sustained releaseformulations.

For oral administration, an M₁R-selective antagonist-antidepressantcombination can be formulated readily by combining with pharmaceuticallyacceptable carriers that are well known in the art. Such carriers enablethe compounds to be formulated as tablets, pills, dragees, capsules,emulsions, lipophilic and hydrophilic suspensions, liquids, gels,syrups, slurries, suspensions and the like, for oral ingestion by apatient to be treated. Pharmaceutical preparations for oral use can beobtained by mixing the compounds with a solid excipient, optionallygrinding a resulting mixture, and processing the mixture of granules,after adding suitable auxiliaries, if desired, to obtain tablets ordragee cores. Suitable excipients are, in particular, fillers such assugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents can beadded, such as a cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds can be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers can be added. All formulations fororal administration should be in dosages suitable for suchadministration.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions can be used, which can optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments can be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds can be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Forinjection, an M₁R-selective antagonist-antidepressant combination can beformulated into preparations by dissolving, suspending or emulsifyingthem in an aqueous or nonaqueous solvent, such as vegetable or othersimilar oils, synthetic aliphatic acid glycerides, esters of higheraliphatic acids or propylene glycol; and if desired, with conventionaladditives such as solubilizers, isotonic agents, suspending agents,emulsifying agents, stabilizers and preservatives. Preferably, acombination of the invention can be formulated in aqueous solutions,preferably in physiologically compatible buffers such as Hanks'ssolution, Ringer's solution, or physiological saline buffer.Formulations for injection can be presented in unit dosage form, e.g.,in ampules or in multi-dose containers, with an added preservative. Thecompositions can take such forms as suspensions, solutions or emulsionsin oily or aqueous vehicles, and can contain formulatory agents such assuspending, stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds can be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions can contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension can also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.Alternatively, the active ingredient can be in powder form forconstitution with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

Systemic administration can also be by transmucosal or transdermalmeans. For transmucosal or transdermal administration, penetrantsappropriate to the barrier to be permeated are used in the formulation.For topical administration, the agents are formulated into ointments,creams, salves, powders and gels. In one embodiment, the transdermaldelivery agent can be DMSO. Transdermal delivery systems can include,e.g., patches. For transmucosal administration, penetrants appropriateto the barrier to be permeated are used in the formulation. Suchpenetrants are generally known in the art. Exemplified transdermaldelivery formulations that can find use in the present invention includethose described in U.S. Pat. Nos. 6,589,549; 6,544,548; 6,517,864;6,512,010; 6,465,006; 6,379,696; 6,312,717 and 6,310,177, each of whichare hereby incorporated herein by reference.

For buccal administration, the compositions can take the form of tabletsor lozenges formulated in a conventional manner.

In addition to the formulations described previously, an M₁R-selectiveantagonist-antidepressant combination of the present invention can alsobe formulated as a depot preparation. Such long acting formulations canbe administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

The pharmaceutical compositions also can comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymerssuch as polyethylene glycols.

4. Kits

The pharmaceutical compositions of the present invention can be providedin a kit. In certain embodiments, a kit of the present inventioncomprises one or more M₁R-selective antagonists and one or moreantidepressants in separate formulations. In certain embodiments, thekits comprise one or more M₁R-selective antagonists and one or moreantidepressants within the same formulation. In certain embodiments, thekits provide the one or more M₁R-selective antagonists and one or moreantidepressants independently in uniform dosage formulations throughoutthe course of treatment. In certain embodiments, the kits provide theone or more M₁R-selective antagonists and one or more antidepressantsindependently in graduated dosages over the course of treatment, eitherincreasing or decreasing, but usually increasing to an efficaciousdosage level, according to the requirements of an individual.

In one embodiment, the kits comprise one or more pharmaceuticalcompositions comprising one or more M₁R-selective antagonists selectedfrom the group consisting of telenzepine and pirenzepine.

In certain embodiments, the kits comprise one or more antidepressantsselected from the group consisting of a selective serotonin reuptakeinhibitor (SSRI), a serotonin-norepinephrine reuptake inhibitor (SNRI),a norepinephrine reuptake inhibitor, a dopamine reuptake inhibitor, anorepinephrine-dopamine reuptake inhibitor (NDRI), aserotonin-norepinephrine-dopamine reuptake inhibitor, and mixturesthereof. In one embodiment, the kits comprise one or more pharmaceuticalcompositions comprising one or more antidepressants selected from thegroup consisting of venlafaxine (racemic or an optical isomer),fluoxetine (racemic or an optical isomer), duloxetine, paroxetine,citalopram, escitalopram, fluvoxamine, S33005, DVS-233 (desvenlafaxine),DVS-233 SR, bupropion, GW353162, sibutramine, atomoxetine and sertraline(or its S-enantiomer, Zoloft®).

In one embodiment, the kit comprises therapeutically effective amountsof telenzepine or pirenzepine and an SSRI. In one embodiment, the kitcomprises therapeutically effective amounts of telenzepine orpirenzepine and citalopram (or escitalopram). In one embodiment, the kitcomprises therapeutically effective amounts of telenzepine orpirenzepine and sertraline (or its S-enantiomer, Zoloft®). In oneembodiment, the kit comprises therapeutically effective amounts oftelenzepine or pirenzepine and fluoxetine (racemic or an opticalisomer). In one embodiment, the kit comprises therapeutically effectiveamounts of telenzepine or pirenzepine and fluvoxamine. In oneembodiment, the kit comprises therapeutically effective amounts oftelenzepine or pirenzepine and paroxetine.

In one embodiment, the kit comprises therapeutically effective amountsof telenzepine or pirenzepine and an SNRI. In one embodiment, the kitcomprises therapeutically effective amounts of telenzepine orpirenzepine and venlafaxine (racemic or an optical isomer). In oneembodiment, the kit comprises therapeutically effective amounts oftelenzepine or pirenzepine and desvenlafaxine. In one embodiment, thekit comprises therapeutically effective amounts of telenzepine orpirenzepine and duloxetine. In one embodiment, the kit comprisestherapeutically effective amounts of telenzepine or pirenzepine andmilnacipran. In one embodiment, the kit comprises therapeuticallyeffective amounts of telenzepine or pirenzepine and mirtazapine.

In one embodiment, the kit comprises therapeutically effective amountsof telenzepine or pirenzepine and bupropion.

EXAMPLES

The following examples are offered to illustrate, but not to limit theclaimed invention.

Example 1

Antidepressant Effects: The tail suspension methodology was used toassess compounds for their antidepressant effects. The methodology wasadapted from the original description by Steru et al. (Steru L, et al.,Psychopharmacol 85:367-70, 1985; Steru L, et al., ProgNeuro-Psychopharmacol & Biol Psychiat 11:659-71, 1987) and latermodifications by Crowley et al. (Crowley J J, et al., Pharmacol BiochemBeh 78(2):269-74, 2004). Seven- to eight-week-old (25-35 grams) male,CD-1 mice were housed for one week prior to testing. Mice (n=8-10 perdose group) were dosed intraperitoneally (ip) or orally (po) with thecompound under investigation, and returned to their home cage for theappropriate pretreatment interval (45-60 min). Using tape, the mice werethen suspended by the tail from a strain gauge. Activity over the next 6minutes was scored by computer as either: 1) Immobility, 2) EscapeBehavior or 3) Major Escape Behavior, based on the intensity ofmovements registered by the strain gauge. Total Immobility wascalculated and expressed in seconds. In this assay, vehicle-treated micetypically spend approximately 30% of the session immobile, whilepretreatment with antidepressants significantly shortens this cumulativeimmobility. Treatment effects are presented in Table 1 and FIGS. 1-6 asboth raw Time Spent Immobile (in seconds±SEM [standard error of themean]) and as % Reduction in Immobility=[1−(Treatment Immobility/VehicleImmobility)]×100%. Similar superscripts in the Dose column of Table 1denote values derived from the same experiment (to facilitatecomparisons between individual treatments and co-administrations).Statistical analyses were performed using a 1-way ANOVA (analysis ofvariance) followed by a Bonferroni multiple comparison test with theoverall alpha set at 0.05. In Table 1, asterisks (*) denote significanteffects compared to vehicle-treated mice, while letters (a or b) denotesignificant effects compared to mice treated with a single compound (“a”for significance from antidepressant and“b” for significance fromtelenzepine). In Table 1, the symbol denotes p<0.05, two symbols denotep<0.01 and three symbols denote p<0.001). The symbols used for denotingstatistical significance may be different in the corresponding figures.

TABLE 1 Vehicle Treatment Dose Immobility Immobility Reduction inCompound (mg/kg) Time (sec) Time (sec) Immobility p Values Telenzepine 5(ip)^(a) 115 + 16 80 ± 14 30% n.s. 5 (ip)^(b) 114 + 19 90 ± 18 21% n.s.5 (ip)^(d) 125 ± 14 159 ± 23  −27%  n.s. 10 (ip)^(c)  97 ± 20 64 ± 1534% n.s. 25 (ip)^(d) 125 ± 14 84 ± 07 33% * 50 (ip)^(d) 125 ± 14 61 ± 1151% *** 60 (po)^(e) 130 ± 21 71 ± 15 45% * 80 (po)^(e) 130 ± 21 82 ± 1837% * 100 (po)^(e) 130 ± 21 59 ± 10 55% ** Pirenzepine 5 (ip)^(f) 123 ±20 137 ± 15  −11%  n.s. 25 (ip)^(f) 123 ± 20 90 ± 17 27% n.s. 50(ip)^(f) 123 ± 20 76 ± 12 38% * Fluoxetine 4 (ip)^(c)  97 ± 20 97 ± 11 0% n.s. 4 (ip)^(g) 146 ± 18 81 ± 16 45% ** 20 (ip)^(g) 146 ± 18 82 ± 1645% ** 40 (ip)^(g) 146 ± 18 53 ± 14 64% *** Sertraline 1 (ip)^(a) 115 ±16 87 ± 14 24% n.s. 5 (ip)^(h) 121 ± 17 63 ± 08 48% ** 20 (ip)^(h) 121 ±17 50 ± 16 59% ** 40 (ip)^(h) 121 ± 17 44 ± 15 64% *** Venlafaxine 3(ip)^(i) 112 ± 15 103 ± 21   8% n.s. 10 (ip)^(i) 112 ± 15 116 ± 20  −4%n.s. 10 (ip)^(b) 114 ± 19 103 ± 15  10% n.s. 30 (ip)^(i) 112 ± 15 31 ±09 72% *** Telenzepine + 10 + 4^(c) (ip)  97 ± 20 45 ± 09 54% **Fluoxetine Telenzepine + 5 + 1^(a) (ip) 115 ± 16 66 ± 12 43% ***Sertraline Telenzepine + 5 + 10^(b) (ip) 114 ± 19 29 ± 09 75% **, aa, bVenlafaxineNote on Effects:

As summarized in Table 1, systemic administration of pirenzepine aloneat 50 mg/kg ip (FIG. 1) or telenzepine alone at 25 mg/kg ip (FIG. 2) or60 mg/kg po (FIG. 3) produces significant reduction in immobility.

When telenzepine is co-administered with an antidepressant, all threecombinations tested display the principle that subactive doses of eachcompound can be combined to produce significant effects that generallyappear synergistic. The telenzepine+venlafaxine combination demonstratedthe greatest efficacy of the tested combinations. Co-administration oftelenzepine and venlafaxine produces a significant (p<0.01) reduction of75%, well beyond the 31% reduction that would be expected from mereadditivity (FIG. 5). Likewise, co-administration of 10 mg/kgtelenzepine+4 mg/kg fluoxetine results in a significant (p<0.01)reduction in immobility of 54%, an effect greater than expected from thecontributions of the individual compounds (FIG. 6). Co-administration oftelenzepine and sertraline produces a significant 43% reduction inimmobility (FIG. 4).

The combinations of selective M₁R-antagonists and antidepressantsdemonstrate that the “effective dose” of the antidepressant compound canbe lowered dramatically by co-administering an M₁R-antagonists (e.g.telenzepine). The venlafaxine dose can be lowered 3 fold (to 10 mg/kg)and still retain efficacy by co-administering 5 mg/kg telenzepine.Compare the 72% reduction in immobility when 30 mg/kg venlafaxine isadministered alone to the 75% reduction in immobility when 10 mg/kgvenlafaxine is co-administered with 5 mg/kg telenzepine. Similarly, thesertraline dose can be lowered 5-fold (to 1 mg/kg) and still retainefficacy by co-administering 5 mg/kg TZP. Compare the 48% reduction inimmobility when 5 mg/kg sertraline is administered alone to the 43%reduction in immobility when 1 mg/kg sertraline is co-administered with5 mg/kg telenzepine. It is estimated that the effective fluoxetine dosecan be lowered approximately 7-fold (to 4 mg/kg) by co-administering 10mg/kg TZP.

It is understood that the examples and embodiments described herein arefor illustrative purposes only and that various modifications or changesin light thereof will be suggested to persons skilled in the art and areto be included within the spirit and purview of this application andscope of the appended claims. All publications, patents, and patentapplications cited herein are hereby incorporated by reference in theirentirety for all purposes.

1. A method for enhancing the antidepressant effect of an antidepressantselected from the group consisting of a selective serotonin reuptakeinhibitor (SSRI) or a serotonin-norepinephrine reuptake inhibitor(SNRI), the method comprising systemically co-administering to anindividual in need thereof telenzepine and a SSRI or a SNRI selectedfrom the group consisting of venlafaxine, sertraline and fluoxetine in atherapeutically effective amount to treat depression, thereby enhancingthe antidepressant effect of the SSRI or the SNRI.
 2. The method ofclaim 1, wherein the SSRI is fluoxetine.
 3. The method of claim 1,wherein the SSRI is sertraline.
 4. The method of claim 1, wherein theSNRI is venlafaxine.
 5. The method of claim 1, wherein the telenzepineis administered in a sustained-release formulation.
 6. An improvedmethod for treating depression with an antidepressant selected from thegroup consisting of a SSRI or an SNRI, the improvement comprisingsystemically co-administering to an individual in need thereoftelenzepine and a SSRI or a SNRI selected from the group consisting ofvenlafaxine, sertraline and fluoxetine in a therapeutically effectiveamount to treat depression.
 7. The method of claim 6, wherein the SSRIis fluoxetine.
 8. The method of claim 6, wherein the SSRI is sertraline.9. The method of claim 6, wherein the SNRI is venlafaxine.
 10. Themethod of claim 6, wherein the telenzepine is administered in asustained-release formulation.